Malaria

PROF DR. HJ. WAN OMA ABDULLAH, JSM

MALARIA
40% of the worlds population live in endemic areas 300-500 million clinical cases per year 1.5-2.7 million deaths (90% Africa) increasing problem (re-emerging disease) resurgence in some areas drug resistance ( mortality)

causative agent = Plasmodium species protozoan parasite member of Apicomplexa (sub-phylum) 4 species infecting human; P.falcifarum (malignant malaria), P.vivax and P.ovale (benign tertian) and P malariae (quartan) transmitted by female anopheline mosquitoes In Malaysia: An.maculatus -most important vector in hills and mountains, An.sundaicus: brackish water, An. balabacensis & A. leucospyrus in deep jungles of Sabah and Sarawak

Primate (Simian) Malaria or Monkey Malaria.

A number of Plasmodium species infect primates. Molecular analysis reveals P. knowlesi of monkey does infect man. P. knowlesi is closely related to P. malariae in term of genetic make up. Morphologically these two species are indistinguishable. Microscopic misidentification as P. knowlesi as P. malariae has led to misdiagnosis of many quartan malaria cases in the past. Clinically, P. knowlesi in man causes symptoms similar with other species of Plasmodium spp.

Epidemiology
Endemic

in most Southeast Asia, Latin America and sub-Saharan Africa (90% in Africa)

Malaysia interior parts of Peninsular Malaysia (P.vivax = P.f), rural areas of Sabah (P.falciparum) and Sarawak (P.vivax)
In

imported cases, foreign /immigrant workers

Sporadic cases Most prevalence forest areas,

land

schemes (eg Felda)

P.f

> P.v > mixed > P.m in Sabah

P.falciparum more

Cases in Malaysia Until 2001:

1997: 26 649 1998 : 13 491
Bilangan Kes

Rajah 1 : Taburan Penyakit Bawaan Vektor Utama di Malaysia 1990-2001

80000 60000 40000 20000 0 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 Tahun
DENGUE FEVER DHF MALARIA

1999 : 11 106 2000 : 12 705 2001 : 11 604

Transmission
sporozoites injected with saliva when mosquitoes feeds on human. enter circulation Blood transfusion Contaminated syringes From mother to fetus (congenital)

Female Anopheles Mosquito

Life Cycle in 2 Hosts:

1.Sporogony: the sporulating sexual cycle in the mosquito 2.Schizogony : asexual cycle in vertebrate host: Exoerythocytic cycle (hepatic cycle); intraerythocytic cycle (erythrocytic cycle) sporozoites injected during mosquito feeding invade liver cells- SCHIZONT exoerythrocytic schizogony (merozoites) merozoites invade RBCs repeated erythrocytic schizogony gametocytes infective for mosquito fusion of gametes in gut sporogony on gut wall in hemocoel sporozoites invade salivary glands

Exoerythrocytic Schizogony
hepatocyte invasion asexual replication 6-15 days 1000-10,000 merozoites no overt pathology

Hyponozoite Forms
some EE forms exhibit delayed replication (i.e, dormant) merozoites produced weeks-to-months after initial infection only P. vivax and P. ovale Relapse Recrudesence : increase in parasite that has persisited at low levels in the blood, e.g. P. malariae

relapse = hypnozoite

recrudescence = subpatentt

Erythrocytic Schizogony
intracellular parasite undergoes trophic phase young trophozoite is ring form P.falcifarum infect RBC of all ages, P.vivax/P.ovale infect reticulocytes. Metabolize host hemoglobin hemozoin (malarial pigment)

P. falcifarum

P.vivax

Erythrocytic Schizogony
nuclear division to become an early schizont stage 6-40 nuclei budding merozoites @ segmenter erythrocyte rupture to release merozoites pyrexia (fever)

erythrocytic schizogony 48 hr in Pf, Pv, Po 72 hr in Pm gametocytes

Trophozoites transform

gametocytes induction is still unknown transformationgametogenesis

Pf : ~10 days others: ~same as schizogony(3-4 days) drug treatment #'s immune response #'s

sexual dimorphism
Microgametocytes (male) Macrogametocytes (female)

Do not cause pathology infective stage for mosquito

Sporogony
The sexual cycle occurs in mosquito (9-21 d); Microgamet (Exflagelation) fusion of micro- and macrogametes zygote ookinete (~24 hr) ookinete penetrate gut epithelium ('transinvasion') ookinete oocyst between epithelium and basal lamina asexual replication sporozoites Released sporozoites migrate through hemocoel sporozoites 'invade' salivary glands

EXFLAGELATION
exflagellation occurs in mosquito gut, whereby Microgametocyte undergo
3X nuclear replication 8 microgametes formed

Invasive Stages:

Merozoite erythrocytes Sporozoite salivary glands hepatocytes Ookinete epithelium

Clinical Features
characterized by acute febrile attacks (malaria paroxysms) periodic episodes of fever alternating with symptom-free periods manifestations and severity depend on species and hosts status immunity, general health, nutritional state, genetics Recrudescence and relapse signify increase in parasites persisted at low level in blood & parasitemia develops from EE stages in liver. Malaria causes severe complications especially P. falciparum; cerebral malaria fatal in young children.

Malaria Paroxysm
The classic periodic fever paroxysm consists : 1. Prodromal : malaise, myalgias, viral like syndrome.2. Cold (chill) stage shivering stage 3. Hot stage : 102-104 0F 4. sweating stage : resolution of fever, severe fatigue and patient go to sleep paroxysms associated with synchrony (cycle) of merozoite release temperature is normal between paroxysms and patient feels well P. falciparum may not exhibit classical paroxysms (continuous fever)

Chills Rigors Fever Perspiration Fatigue Headache Delirium Confusion Coma Shortness of breath Anemia Splenomegaly Black urine

Disease Severity
Pv Po Pm Pf
moderate Paroxysm mild to mild severe Severity moderate to severe Average 50,00020,000 9,000 6,000 500,000 (per mm3) Maximum 50,000 30,000 20,000 2,500,000 (per mm3) Anemia ++ + ++ ++++ Duration Disease 3-8 w 2-3 w 3-24 w 2-3 w Infection 5-8 y* 12-20 m* >20 y 6-17 m Complications renal cerebral** *true relapses ( recrudescence) due to dormant hypnozoite stage in liver **plus many other organs

Treatment
Choose the appropriate blood/tissue schizonticide; need to expect resistance pattern of the organism, severity of infection, and patients background eg. immune status. In severe cases, patient will need to be closely monitored for complications such as hypoglycemia, anemia, seizures, septicemia, renal failure, acidosis and respiratory failure. Indication of blood transfusions, hemodialysis, mechanical ventilation and antibiotics.

Antimalarial Drugs

Treatment: to clear parasitemia

Chloroquine Fansidar (Sulfadoxine/

Prophylaxis: to protect from infection

Chloroquine

pyrimetamine) Quinine Artesunate Doxycycline Malarone Primaquine Artemesinin derivatives; artesunate, artemether and arte-ether

Daraprim
Proguanil

Chloroquine Resistance
Frequent in P.falcifarum in most parts of world outside of Central America and the Caribbean P.vivax resistance in SEA and Amazon Multiple drug resistant strains exist especially in Thailand and border areas.

Summary on Antimalaria Chemotherapy

1.

2. 3.

6.

7.

Chloroquine phosphate- Treatment of uncomplicated attacks (except resistant P. falciparum). Alternatively, Amodiaquine dihydrochloride Prevention of relapses Primaquine phosphate; Primaquine is the only drug effective against persisting EE liver stages. Infections of P. f resistant to chloroquine are treated by combined therapy: a. Quinine sulfate pyrimethaminesulfadiazine or b. Quininetetracycline/clindamycin. Mefloquine is effective against P..f that is resistant to all known drugs, including quinine

Laboratory Diagnosis
Thin

and thick blood film;

shape and size of trophozoite, schizont, gametocyte, size of RBCs which contain parasites ;P.vivax and P. ovale (infect younger RBC, enlargement of RBC) Metabolic debris in RBC around the parasites (Schuffners dot in P.vivax infection)
QBC-flourescence

microscopy

P. malariae trophozoite (band form)

and

P. ovale

Indirect Diagnosis
Serological:

antibody/antigen detection assay; ELISA, IFAT Molecular Bio.Techniques; PCR, DNA probe (mainly as research tools)

Control and Prevention

Personal protection against vectors

Evening

and night behavior (bite at night) Mosquito nets Mosquito repellants

Vector Control

Biological control

Bacteria: Bacillus thuringiensis, Bacillus sphaericus

Chemical control
Larvicidal
Organophosphates-temephos,Abate 500E

Adulticidal
DDT residual spraying once in 6 month,endemic area once in 3 month, nowadays DDT has been banned in many countries Malathion Phyrethroids; impregnated bednets Thermal fogging or ultra-low-volume (ULV)

Chemoprophylaxis: for those entering malarious areas.

Should be given 1-2 weeks before traveling to endemic areas. Should be continued during travel and after leaving endemic areas.

Chloroquine Doxycycline Mefloquine

REVIEW QUESTIONS
MCQ (T & F) 1. The following are invasive stages of human malarial parasites A. Ookinete B. Sprozoite C. Merozoite D. Trophozoite E. Gametocytes 2. The following are clinical symptoms of malaria A. Anemia B. Splenomegaly C. Fever D. Keratitis E. Adenolymphagitis

3. The following are routinely performed diagnostic procedures for malaria. A. Polymerase Chain Reaction B. DNA probe C. Immunosassay D. Microscopic detection in blood smears E. Liver biopsy 4. Regarding malarial parasites: A. Febrile paroxysm in quartan malaria is every 48 hours interval. B. Accurate identification of species is by morphological features. C. P. knowlesi, a monkey malaria was misdiagnosed as P. malariae in the past. D. Malignant tertian malaria is caused by P. vivax. E. Chloroquin phosphate is effective against liver schizont.

OSPE
An American tourist returned to USA after a vacation in Sarawak. Few months later he experienced severe febrile attacks and was admitted to ICU of Mayo Clinic. Microscopic examination of his blood smear revealed infected RBC as shown.
a. b.

c.

Identify the parasite (genus and species) Explain the pathogenesis of fever in this patient. List two clinical complications that could arise from infection with this parasite.